Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells

Abstract

Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a nongenetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM. Based on analyses of molecular and histologic markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells-mainly of chief cells.

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

“…In wild-type mice (either with or without rapamycin), we did not detect substantial apoptotic death of the chief cells, consistent with our previous observations that death in HD-Tam is essentially confined to parietal cells (Huh et al, 2012;Radyk et al, 2018; Fig EV1). In wild-type mice (either with or without rapamycin), we did not detect substantial apoptotic death of the chief cells, consistent with our previous observations that death in HD-Tam is essentially confined to parietal cells (Huh et al, 2012;Radyk et al, 2018; Fig EV1).…”

“…The lack of proliferation did not affect SPEM induction, as defined by cells co-stained with GSII and the chief cell marker, GIF (Fig 2A and B). That cells expressing molecular features of metaplasia can arise in the absence of proliferation is consistent with multiple previous reports showing that chief cells can give rise directly to SPEM cells without contribution from the isthmal stem cell (Nam et al, 2010;Radyk et al, 2018). That cells expressing molecular features of metaplasia can arise in the absence of proliferation is consistent with multiple previous reports showing that chief cells can give rise directly to SPEM cells without contribution from the isthmal stem cell (Nam et al, 2010;Radyk et al, 2018).…”

“…To determine whether mTORC1 activity is modulated in human disease states, we first examined a database of stomach tissues from human patients exhibiting metaplastic response to H. pylori infection, previously compiled at Washington University (Lennerz et al, 2010;Radyk et al, 2018). A representative region from this dataset is shown in Fig 3A. As in mice, morphologically normal chief cells showed high pS6.…”

“…A representative region from this dataset is shown in Fig 3A. As in mice, morphologically normal chief cells showed high pS6. In lesions that had histological features of cells undergoing acute conversion to SPEM (what we have previously termed "hybrid SPEM" (Lennerz et al, 2010;Radyk et al, 2018) based on examination of a large dataset of SPEM lesions), pS6 levels were high ( Fig 3A). In lesions that had histological features of cells undergoing acute conversion to SPEM (what we have previously termed "hybrid SPEM" (Lennerz et al, 2010;Radyk et al, 2018) based on examination of a large dataset of SPEM lesions), pS6 levels were high ( Fig 3A).…”

“…Figure 3A is a representative image from a qualitative analysis of 44 separate curated gastric clinical samples that have been previously described (Lennerz et al, 2010;Radyk et al, 2018). Figure 3A is a representative image from a qualitative analysis of 44 separate curated gastric clinical samples that have been previously described (Lennerz et al, 2010;Radyk et al, 2018).…”